A safe and effective vaccine for HIV is critically needed to combat the worldwide scourge of AIDS. While the correlates of immune protection have yet to be clearly defined, either for protective or therapeutic vaccines, it is widely believed that systemic and mucosal CD4+ and CD8+ T cell and humoral immunity are important. How sufficiently broad, potent, and sustained responses, particularly for mucosal, can be elicited has yet to be determined, and this represents a critical gap in our understanding. Dendritic cells (DC) represent the interface between innate and adaptive immunity and are among the most potent and important components in generating adaptive immune responses. The main action of a vaccine is to load a DC with antigen and deliver an activating stimulus. Our laboratory has demonstrated that mRNA loaded DC could induce CD4+, CD8+, and antibody responses. We identified the mechanisms whereby RNA activates innate immune receptors and developed RNA that avoids their activation and yields superior translational efficiency. Our hypotheses is that delivery of HIV antigen-encoding modified mRNA to DC in oral mucosa offers a uniquely flexible and potent approach to immunization, that DC activation after RNA delivery can be controlled to generate the desired immune responses (e.g. helper, cytotoxic, suppressor, humoral, and mucosal), and that this approach can be exploited for the development of orally delivered HIV vaccines. The aim of this proposal is to optimize RNA uptake by oral mucosal DC, enhance antigen presentation by DC of mRNA-encoded antigen, develop approaches to modulate the type of immune response induced, and establish proof-of-concept evidence for efficacy in HIV. In these studies, we will combine two powerful approaches currently in use in vaccine design to develop an orally deliverable vaccine, DC targeted vaccines and mRNA encoded antigen, to develop an orally deliverable HIV vaccine that induces systemic, and likely more important for prevention of transmission, mucosal immunity. The relevance of this proposal is that it leads to the development of an easily deliverable vaccine against HIV that will develop mucosal immunity. Mucosal immunity is the first immune response to encounter HIV during mucosal transmission and, thus, has a better chance of stopping infection.